Genetic Variant PCSK4:p.Cys649Phe (chr19-1482081-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_017573.5(PCSK4):c.1946G>T(p.Cys649Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,552,464 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0054 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 86 hom. )

Consequence

PCSK4
NM_017573.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.832

Variant links:

Genes affected

PCSK4 (HGNC:8746): (proprotein convertase subtilisin/kexin type 4) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]

PCSK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010106891).

BP6

Variant 19-1482081-C-A is Benign according to our data. Variant chr19-1482081-C-A is described in ClinVar as [Benign]. Clinvar id is 2648935.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 86 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK4	NM_017573.5 link	c.1946G>T	p.Cys649Phe	missense_variant	Exon 15 of 15	ENST00000300954.10	NP_060043.2	Q6UW60-1A0A140VJQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK4	ENST00000300954.10 link	c.1946G>T	p.Cys649Phe	missense_variant	Exon 15 of 15	1	NM_017573.5	ENSP00000300954.5		Q6UW60-1

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

826

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00991

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00474

AC:

704

AN:

148602

Hom.:

AF XY:

0.00463

AC XY:

376

AN XY:

81296

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00985

Gnomad OTH exome

AF:

0.00577

GnomAD4 exome

AF:

0.00990

AC:

13866

AN:

1400162

Hom.:

Cov.:

AF XY:

0.00966

AC XY:

6688

AN XY:

692098

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00268

Gnomad4 ASJ exome

AF:

0.000674

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000250

Gnomad4 FIN exome

AF:

0.00270

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.00989

GnomAD4 genome

AF:

0.00542

AC:

826

AN:

152302

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

354

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00991

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00706

Hom.:

Bravo

AF:

0.00547

ESP6500AA

AF:

0.00101

AC:

ESP6500EA

AF:

0.00852

AC:

ExAC

AF:

0.00230

AC:

257

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCSK4: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.74

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.53

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.0

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.94

Vest4

0.55

MVP

0.60

MPC

0.79

ClinPred

0.098

GERP RS

2.8

Varity_R

0.72

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over